Abstract：
Inactivating alterations in the SWItch/Sucrose NonFermentable (SWI/SNF) Chromatin Remodeling Complex subunits have been described in multiple tumor types. Recent studies focused on SMARC subunits of this complex to understand their relationship with tumor characteristics and therapeutic opportunities. To date, pancreatic cancer with these alterations has not been well studied, although isolated cases of undifferentiated carcinomas have been reported. Herein, we screened 59 pancreatic undifferentiated carcinomas for alterations in SWI/SNF complex-related (SMARCB1 [BAF47/INI1], SMARCA4 [BRG1], SMARCA2 [BRM]) proteins and/or genes using immunohistochemistry and/or next-generation sequencing. Cases with alterations in SWI/SNF complex-related proteins/genes were compared with cases without alterations, as well as with 96 conventional pancreatic ductal adenocarcinomas (PDAC). In all tumor groups, mismatch repair and PD-L1 protein expression were also evaluated. Thirty of 59 (51%) undifferentiated carcinomas had a loss of SWI/SNF complex-related protein expression or gene alteration. Twenty-seven of 30 (90%) SWI-/SNF-deficient undifferentiated carcinomas had rhabdoid morphology (vs 9/29 [31%] SWI-/SNF-retained undifferentiated carcinomas; P < .001) and all expressed cytokeratin, at least focally. Immunohistochemically, SMARCB1 protein expression was absent in 16/30 (53%) cases, SMARCA2 in 4/30 (13%), and SMARCA4 in 4/30 (13%); both SMARCB1 and SMARCA2 protein expressions were absent in 1/30 (3%). Five of 8 (62.5%) SWI-/SNF-deficient undifferentiated carcinomas that displayed loss of SMARCB1 protein expression by immunohistochemistry were found to have corresponding SMARCB1 deletions by next-generation sequencing. Analysis of canonical driver mutations for PDAC in these cases showed KRAS (2/5) and TP53 (2/5) abnormalities. Median combined positive score for PD-L1 (E1L3N) was significantly higher in the undifferentiated carcinomas with/without SWI/SNF deficiency compared with the conventional PDACs (P < .001). SWI-/SNF-deficient undifferentiated carcinomas were larger (P < .001) and occurred in younger patients (P < .001). Patients with SWI-/SNF-deficient undifferentiated carcinoma had worse overall survival compared with patients with SWI-/SNF-retained undifferentiated carcinoma (P = .004) and PDAC (P < .001). Our findings demonstrate that SWI-/SNF-deficient pancreatic undifferentiated carcinomas are frequently characterized by rhabdoid morphology, exhibit highly aggressive behavior, and have a negative prognostic impact. The ones with SMARCB1 deletions appear to be frequently KRAS wild type. Innovative developmental therapeutic strategies targeting this genomic basis of the SWI/SNF complex and the therapeutic implications of EZH2 inhibition (NCT03213665), SMARCA2 degrader (NCT05639751), or immunotherapy are currently under investigation.
摘要：
已在多种肿瘤类型中描述了SWItch/蔗糖不可发酵（SWI/SNF）染色质重塑复合物亚基的失活改变。最近的研究集中在这种复合物的SMARC亚基上，以了解它们与肿瘤特征和治疗机会的关系。迄今为止,有这些改变的胰腺癌还没有得到很好的研究，尽管已报道了未分化癌的孤立病例。在这里，我们筛选了59个胰腺未分化癌的SWI/SNF复合物相关的改变[SMARCB1（BAF47/INI1），SMARCA4(BRG1),SMARCA2（BRM）]蛋白质和/或基因使用免疫组织化学（IHC）和/或下一代测序（NGS）。将SWI/SNF复合物相关蛋白/基因改变的病例与无改变的病例进行比较，以及96例常规胰腺导管腺癌（PDAC）。在所有肿瘤组中，还评估了MMR和PD-L1蛋白表达。59例（51％）未分化癌中有30例丧失了SWI/SNF复合物相关蛋白表达或基因改变。30例（90％）SWI/SNF缺陷型未分化癌中有27例具有横纹肌形态[与9/29（31％）SWI/SNF保留的未分化癌；p<0.001]且均表达细胞角蛋白，至少集中。免疫组织化学，16/30(53%)例SMARCB1蛋白表达缺失,SMARCA2在4/30（13%），SMARCA4在4/30（13％）；SMARCB1和SMARCA2蛋白表达均在1/30（3％）中缺失。通过IHC显示SMARCB1蛋白表达缺失的8个（62.5％）SWI/SNF缺陷型未分化癌中的5个被NGS发现具有相应的SMARCB1缺失。这些病例中PDAC的典型驱动突变分析显示KRAS(2/5)和TP53(2/5)异常。与常规PDAC相比，在有/无SWI/SNF缺乏的未分化癌中，PD-L1的CPS中位数（E1L3N）明显更高（p<0.001）。SWI/SNF缺乏的未分化癌较大（p<0.001），发生在年轻患者中（p<0.001）。与SWI/SNF保留的未分化癌（p=0.004）和PDAC（p<0.001）患者相比，SWI/SNF缺陷型未分化癌患者的总体生存率较差。我们的发现表明，SWI/SNF缺陷型胰腺未分化癌通常以横纹肌形态为特征，表现出高度攻击性的行为，并对预后产生负面影响。具有SMARCB1缺失的那些似乎经常是KRAS野生型。针对SWI/SNF复合物的基因组基础和EZH2抑制的治疗意义的创新发展治疗策略（NCT03213665），SMARCA2降解器(NCT05639751),或免疫疗法目前正在研究中。
